Diabetes is a disease having a chronically high blood glucose level as the main symptom, which is generated by absolute or relative insufficiency of insulin action. Clinically, it is roughly divided into insulin dependent diabetes mellitus (IDDM) and non insulin dependent diabetes mellitus (NIDDM). In the non insulin dependent diabetes mellitus (NIDDM), lowering of insulin secretion from pancreatic β cells is one of the main causes of the onset of the disease, and particularly a high blood glucose level after meal is recognized due to an initial stage insulin secretion disorder.
Recently, it has been confirmed by large scale clinical tests that correction of high blood glucose level after meal is important for the onset and suppression of diabetic complications. In addition, it has been reported that arteriosclerosis is generated at a stage of only high blood glucose level after meal, and that continuation of slightly high blood glucose level after meal increases mortality rate caused by a vascular disease and the like. It shows that the high blood glucose level after meal is an independent risk factor of cardiovascular death even when it is slight. Based on the above information, necessity of a drug therapy for high blood glucose level after meal has been recognized.
Currently, sulfonylurea (SU) preparations are the main stream as the insulin secretion promoter, but it is known that it is apt to cause hypoglycemia and induces secondary invalidity due to exhaustion of the pancreas in the case of its long-time administration. In addition, the SU preparations are effective in controlling blood glucose level during meal, but it is difficult to suppress over blood glucose level after meal.
GPR40 is a G protein-coupled receptor which has been identified as a fatty acid receptor and is highly expressed in β cells of the pancreas, and it has been reported that it is concerned in the insulin secretory action of fatty acid (Non-patent Reference 1).
Accordingly, since correction of high blood glucose level after meal is expected based on its insulin secretion promoting action, the GPR40 receptor agonist is useful as an agent for preventing/treating insulin dependent diabetes mellitus (IDDM), non insulin dependent diabetes mellitus (MDDM) and a border type (abnormal glucose tolerance and fasting blood glucose level) mild case diabetes.
Patent Reference 1 reports that the compound represented by the formula (A) including a broad range of compounds has the GPR40 receptor-controlling action and is useful as an insulin secretion promoter or an agent for preventing/treating diabetes.
However, there is no illustrative disclosure on a compound having oxadiazolidinedione structure.
(In the formula, ring P represents an aromatic ring which may have a substituent, and ring Q an aromatic ring which may further have a substituent other than
X and Y spacers, and
a group capable of releasing a cation.)
Patent Reference 2 reports that the compound represented by the formula (B) has the GPR40 receptor-controlling action and is useful as an insulin secretion promoter or an agent for preventing/treating of diabetes. However, there is no illustrative disclosure on a compound having oxadiazolidinedione structure.
(See Said Official Gazette for Symbols in the Formula.)
Patent Reference 3 reports that the compound represented by the formula (C) has the GPR40 receptor-controlling action and is useful as an insulin secretion promoter or an agent for preventing/treating diabetes. However, there is no illustrative disclosure on a compound having oxadiazolidinedione structure.
(See Said Official Gazette for Symbols in the Formula.)
Patent Reference 4 reports that the oxadiazolidinedione compound represented by the formula (D) has the plasminogen activation inhibitor (PAI)-1 inhibiting action and is useful in treating thrombus, atrial fibrillation, myocardial ischemia, diabetes and the like. However, there is no description on its action for the GPR40 receptor.
(In the formula, X represents
See said official gazette for other symbols.)
Patent Reference 5 reports that the compound having two oxadiazolidinedione structures, represented by the formula (E), has an action to enhance insulin sensitivity and is useful in treating diabetes. However, there is no description on its action on the GPR40 receptor.
(See Said Official Gazette for Symbols in the Formula.)
Patent Reference 6 reports that the oxazolidinedione compound represented by the formula (F) has blood glucose level-lowering action and blood lipid-lowering action and is useful in treating diabetes. However, the ring which corresponds to the oxadiazolidinedione of the present invention is oxazolidinedione. In addition, there is no description on its action for the GPR40 receptor.
(See Said Official Gazette for Symbols in the Formula.)
Patent Reference 7 reports that the oxadiazolidinedione compound represented by formula (G) has the blood glucose level-lowering action and is useful in treating diabetes. However, the ring which corresponds to the ring A of the present invention is oxadiazole ring. In addition, there is no description on its action on the GPR40 receptor.
(See Said Official Gazette for Symbols in the Formula.)
Patent Reference 8 reports that the compound represented by formula (H) has the blood glucose level-lowering action and is useful in treating diabetes. However, there is no description on its action on the GPR40 receptor.
(See Said Official Gazette for Symbols in the Formula)
Patent Reference 9 reports that the oxadiazolidinedione compound represented by formula (J) has the blood glucose level-lowering action and is useful in treating diabetes. However, the ring which corresponds to the ring A of the compound of the present invention is oxazole or thiazole. In addition, there is no description on its action on the GPR40 receptor.
(X in the formula represents oxygen atom or sulfur atom. See said official gazette for other symbols.)
Patent Reference 10 reports that the compound represented by formula (K) is useful for hyperlipemia, hyperglycemia, obesity, and the like. However, the ring which corresponds to the ring A of the compound of the present invention is morpholine or thiomorpholine. In addition, there is no description on its action on the GPR40 receptor.
(A in the formula represents oxygen atom or sulfur atom. See said official gazette for other symbols.)
Non-patent Reference 2 reports that the oxadiazolidinedione compound represented by formula (L) has the blood glucose level-lowering action and is useful in treating diabetes. However, the ring which corresponds to the ring A of the compound of the present invention is (di)azole ring. In addition, there is no description on its action on the GPR40 receptor.
(In the formula, X represents O, S or N, Y represents C or N, and n is 1 or 2. See said reference for other symbols.)    Non-patent Reference 1: Nature, (England), 2003, vol. 422, p. 173-176    Non-patent Reference 2: European Journal of Medicinal Chemistry, (France), 2001, vol. 36, p. 31-42    Patent Reference 1: International Publication No. 2004/041266    Patent Reference 2: International Publication No. 2005/063729    Patent Reference 3: International Publication No. 2005/063725    Patent Reference 4: International Publication No. 2005/030203    Patent Reference 5: International Publication No. 94/25448    Patent Reference 6: JP-A-2000-212174    Patent Reference 7: International Publication No. 95/30664    Patent Reference 8: International Publication No. 97/41097    Patent Reference 9: U.S. Pat. No. 5,480,896    Patent Reference 10: JP-A-7-2848